Inhibitors of IAP

Abstract

Novel inhibitors of IAP that are useful as therapeutic agents for treating malignancies and have the general formula I:wherein R1, R2, R3, R4, R5 and R6 are as described herein.

We claim: 
     
       1. A method for inhibiting the binding of an inhibitor of apoptosis (IAP) protein to a caspase protein comprising a combination therapy of contacting said IAP protein with a compound according to formula I and applying a further therapy to the IAP protein: 
       
         
           
           
               
               
           
         
         wherein
 Ph is phenyl; 
 R 1  is C 3-7  cycloalkyl; and 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each independently in each occurrence H or 
 C 1-6  alkyl; 
 
         or a pharmaceutically acceptable salt thereof; 
         wherein the further therapy comprises radiation therapy and/or contacting with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. The method according to  claim 1 , wherein R 2 -R 6  are each independently H or methyl. 
     
     
       3. The method according to  claim 1 , wherein R 1  is cyclohexyl. 
     
     
       4. The method according to  claim 1 , wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof. 
     
     
       5. The method according to  claim 1 , wherein said further therapy is radiation therapy. 
     
     
       6. The method according to  claim 1 , wherein said further therapy is contacting the IAP protein with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises: a cytostatic compound; an antineoplastic compound; a chemotherapy compound; a compound which sensitizes or induces apoptosis by binding to death receptors; an agent that modulates a protein kinase; and/or an agent that modulates non-kinase biological targets or processes. 
     
     
       7. A method for treating a disease or condition associated with the overexpression of an inhibitor of apoptosis (IAP) in a mammal, comprising a combination therapy of administering to said mammal an effective amount of a compound according to formula I and applying a further therapy to said mammal: 
       
         
           
           
               
               
           
         
         wherein
 Ph is phenyl; 
 R 1  is C 3-7  cycloalkyl; and 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each independently in each occurrence H or 
 C 1-6  alkyl; 
 
         or a pharmaceutically acceptable salt thereof; 
         wherein the further therapy comprises radiation therapy and/or administering one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof. 
       
     
     
       8. The method according to  claim 7 , wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof. 
     
     
       9. The method according to  claim 7 , wherein R 2 -R 6  are each independently H or methyl. 
     
     
       10. The method according to  claim 7 , wherein R 1  is cyclohexyl. 
     
     
       11. The method according to  claim 7 , wherein said further therapy is radiation therapy. 
     
     
       12. The method according to  claim 7 , wherein said further therapy is administering one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises: a cytostatic compound; an antineoplastic compound; a chemotherapy compound; a compound which sensitizes or induces apoptosis by binding to death receptors; an agent that modulates a protein kinase; and/or an agent that modulates non-kinase biological targets or processes. 
     
     
       13. A method of inducing apoptosis in a cell comprising a combination therapy of introducing into said cell a compound according to formula I and applying a further therapy to said cell: 
       
         
           
           
               
               
           
         
         wherein
 Ph is phenyl; 
 R 1  is C 3-7  cycloalkyl; and 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each independently in each occurrence H or 
 C 1-6  alkyl; 
 
         or a pharmaceutically acceptable salt thereof; 
         wherein the further therapy comprises radiation therapy and/or contacting with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof. 
       
     
     
       14. The method according to  claim 13 , wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof. 
     
     
       15. The method according to  claim 13 , wherein R 2 -R 6  are each independently H or methyl. 
     
     
       16. The method according to  claim 13 , wherein R 1  is cyclohexyl. 
     
     
       17. The method according to  claim 13 , wherein said further therapy is radiation therapy. 
     
     
       18. The method according to  claim 13 , wherein said further therapy is contacting the cell with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises: a cytostatic compound; an antineoplastic compound; a chemotherapy compound; a compound which sensitizes or induces apoptosis by binding to death receptors; an agent that modulates a protein kinase; and/or an agent that modulates non-kinase biological targets or processes. 
     
     
       19. A method of sensitizing a cell to an apoptotic signal comprising a combination therapy of introducing into said cell a compound according to formula I and applying a further therapy to said cell: 
       
         
           
           
               
               
           
         
         wherein
 Ph is phenyl; 
 R 1  is C 3-7  cycloalkyl; and 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each independently in each occurrence H or 
 C 1-6  alkyl; 
 
         or a pharmaceutically acceptable salt thereof; 
         wherein the further therapy comprises radiation therapy and/or contacting with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof. 
       
     
     
       20. The method according to  claim 19 , wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof. 
     
     
       21. The method according to  claim 19 , wherein R 2 -R 6  are each independently H or methyl. 
     
     
       22. The method according to  claim 19 , wherein R 1  is cyclohexyl. 
     
     
       23. The method according to  claim 19 , wherein said further therapy is radiation therapy. 
     
     
       24. The method according to  claim 19 , wherein said further therapy is contacting the cell with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises: a cytostatic compound; an antineoplastic compound; a chemotherapy compound; a compound which sensitizes or induces apoptosis by binding to death receptors; an agent that modulates a protein kinase; and/or an agent that modulates non-kinase biological targets or processes. 
     
     
       25. A method for treating cancer in a mammal, comprising a combination therapy of administering to said mammal an effective amount of a compound according to formula I and applying a further therapy to said mammal: 
       
         
           
           
               
               
           
         
         wherein
 Ph is phenyl; 
 R 1  is C 3-7  cycloalkyl; and 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each independently in each occurrence H or 
 C 1-6  alkyl; 
 
         or a pharmaceutically acceptable salt thereof; 
         wherein the further therapy comprises radiation therapy and/or administering one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof. 
       
     
     
       26. The method according to  claim 25 , wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof. 
     
     
       27. The method according to  claim 25 , wherein R 2 -R 6  are each independently H or methyl. 
     
     
       28. The method according to  claim 25 , wherein R 1  is cyclohexyl. 
     
     
       29. The method according to  claim 25 , wherein said further therapy is radiation therapy. 
     
     
       30. The method according to  claim 25 , wherein said further therapy is administering one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises: a cytostatic compound; an antineoplastic compound; a chemotherapy compound; a compound which sensitizes or induces apoptosis by binding to death receptors; an agent that modulates a protein kinase; and/or an agent that modulates non-kinase biological targets or processes.